The AIM-HIGH trial will test whether combined dyslipidemic therapy (to raise HDL-C and lower both triglycerides and LDL-C) with simvastatin plus extended- release niacin (niacin) will reduce cardiovascular events more than LDL-lowering alone with simvastatin in patients with cardiovascular disease. Despite the widespread use of niacin in clinical practice for decades, we have remarkably little understanding of its mechanism of action in human beings. We are thus proposing an ancillary study to the AIM-HIGH trial designed to address three broad questions related to the mechanism of action of niacin. 1) Is there a pharmacogenetic interaction between variation in the gene encoding for the niacin receptor (GPR109A) and the effect of niacin on lipids in AIM-HIGH? 2) Is there a pharmacogenetic interaction between GPR109A and niacin on major cardiovascular events in AIM-HIGH? 3) Is there a pharmacogenetic interaction between GPR109A and niacin on adverse biochemical and clinical responses in AIM-HIGH? 4) Is there a pharmacogenetic interaction between niacin and other candidate genes involved in the regulation of five major metabolic pathways that are likely to play an important role in mediating the biochemical and/or clinical responses (as described in the first 3 aims) to niacin. We will take a genomic approach to answering these questions, based on identifying associations between common variations in candidate genes and drug response. We will make use of existing data collected in AIM-HIGH, including all demographic, adverse event, drug tolerability, a broad range of plasma lipoprotein measures already being collected in the main trial, and clinical outcomes data. Genomic analyses will be performed on DNA, which is already being collected and stored in the main AIM-HIGH trial. This ancillary study to the AIM-HIGH trial is designed to find out more information about how niacin exerts its affects on lipoproteins. We also seek to find out more information about how the adverse effects of niacin occur and how genetic diversity may play a role in individual responses to niacin. (End of Abstract)